In topical administration of medicaments to the eye, a variety of factors can be important. These factors include comfort, consistency and accuracy of dosage, type and time of any vision interference, ease of administration, and timing of delivery. Prior ophthalmic delivery vehicles have suffered drawbacks in one or more of those areas.
For example, eye drops in the form of aqueous solutions or suspensions are typically rapidly washed away by the eye's tear fluid. Ointments or creams blur the vision, and also have comparatively short residence times in the eye. Gelatin lamellae or other films or sheets, ocular inserts and non-aqueous suspensions and emulsions all can cause immediate pain and continuing discomfort and can also interfere with vision.
Consequently, there is a constant search for new and improved methods and systems for the topical administration of medicaments to the eye. In recent years, much attention has been directed to polymeric based topical ophthalmic delivery systems. Some of the polymeric systems have proved useful for various applications. However, few systems, if any, are particularly suitable for all applications. Thus, new systems are continuously being developed.
Schoenwald et 3.1,, in U.S. Pat. Nos. 4,271,143 and 4,407,792, issued Jun. 2, 1981 and Oct. 4, 1983; respectively, discloses ophthalmic delivery systems containing an aqueous dispersion of an ophthalmic drug and a high molecular weight polymer. The systems are in the form of a highly viscous, i.e., 40,000 to 300,000 cps, gel having a preferred pH of from about 4.5 to about 8.5. However, at a viscosity of above 30,000 cps, reliable administration in drop form is at best difficult to achieve and at worst impossible. Thus, these systems are difficult to administer so as to provide consistent, accurate dosages and may be uncomfortable to administer as well.
Toko, in UK Patent Application No. GB 2007091A, describes an ophthalmic composition comprising a carboxy vinyl polymer in the form of a gel having a pH of 5 to 8 and a viscosity of 1,000 to 100,000 cps. The relatively low viscosity preparations having viscosities of 1,000 to 10,000 are stated to have good flowability and to be amenable to application by drops directly into the mucous membrane around the eyeball. The preparations having viscosities of from 10,000 to 100,000 cps are stated to be amenable to application to the eyelids like conventional ointments. However, in both higher and lower viscosity situations it is stated that the tears liquify the gel. Consequently, the use of sodium chloride in the preparation is recommended for sustained efficiency because sodium chloride is said to delay breakdown of the gel when the compositions are applied to the mucous membrane of the eye. However, the sodium chloride is also said to convert the gel to a liquid with a great reduction in viscosity. Therefore, when sodium chloride is added to the composition, increased polymer amounts are recommended to compensate for such-viscosity reduction due to the addition of sodium chloride.
Although delaying breakdown of a gel of a given viscosity by using the Toko teachings might have some benefits, it is that given viscosity which will influence whether reliable administration in drop form is achievable or whether ointment-like administration, together with its dosage problems, will be dictated. Whether the alleged sustained efficiency benefit said in Toko to be associated with a sodium chloride additive could even be accomplished at viscosities suitable for drop administration is far from clear from Toko. Nevertheless, even if such a benefit could be obtained with a Toko formulation at a viscosity for administration by drops, the fact that the starting viscosity is at a level low enough to even permit administration by drops is itself limiting on the so-called sustained efficiency. Indeed, as stated in the Toko document, when the preparations are applied, the tears liquify the gel. The sodium chloride merely is said to delay that breakdown.
Haslam et al., in U.S. Pat. No. 4,474,751, issued Oct. 2, 1984, discloses an ophthalmic drug delivery system utilizing thermosetting gels. The drug delivery system consists of a clear liquid which forms a semi-solid gel at human body temperatures. The sol-gel transition temperature and rigidity of the gel may be modified by changes in polymer concentration, adjustment of the pH and/or ionic strength of the solution. The polymers used in the delivery system include tetra substituted derivatives of various substituted unsaturated alkyl diamines, such as ethylene diamine and propylene dime. The substituted diamine systems used are of a pH of from 2 to 9, preferably 4 to 8.
In contrast to the diamine based systems disclosed by Haslam at., Davis et al,, in International Applications WO 89/06964 and WO 92/00044, published under the Patent Cooperation Treaty on Aug. 10, 1989 and Jan. 9, 1992, respectively, discloses new topical medicament delivery systems that are administrable in drop form and, after coming into contact with the eye's tear fluid, rapidly gel in the eye to a substantially greater viscosity than the viscosity of the administered drop.
The Davis et al, topical ophthalmic medicament delivery systems include an aqueous suspension containing from about 0.1% to about 6.5% by weight, based on the total weight of the suspension, of a carboxyl-containing polymer prepared by polymerizing one or more carboxyl-containing monoethylenically unsaturated monomers and less than about 5% by weight of a cross-linking agent. The polymer has an average particle size of not more than about 50 microns in equivalent spherical diameter and are lightly cross-linked such that the suspension is administrable in drop form. The suspensions are at a relatively low pH, i.e., a pH of from 3 to 6.5, prior to administration and undergo increased gellation upon contact with the eye.
Davis et al., in International Application WO 92/00707, published under the Patent Cooperation Treaty on Jan. 23, 1992, discloses another new topical medicament delivery system containing an aqueous ophthalmic gel suspension useful for dry eye applications and administrable to the eye in drop form such that it releases water and one or more ophthalmic vasoconstrictors contained therein. The dry eye delivery systems containing an ophthalmic vasoconstrictor include an aqueous suspension containing from about 0.1% to about 6.5% by weight, based on the total weight of the suspension, of a carboxyl-containing polymerprepared by polymerizing one or more carboxyl-containing monoethylenically unsaturated monomers and less than about 5% by weight of a cross-linking agent. The suspensions have a pH of from about 6.6 to about 8.0.
Although each of the foregoing ophthalmic formulations can be acceptable for some purposes in connection with the delivery of certain ophthalmic medicaments, they can be unacceptable for other purposes. For example, problems of ease and reliability of administration, comfort and/or sustained efficacy can be encountered.